SREBP signaling regulates transcriptions of genes necessary for the homeostasis of fatty acids and cholesterol in the cell, which is a key factor for cellular wellbeing and proliferation. Accordingly, the abrogation of SREBP signaling is associated with numerous pathological conditions ranging from cardiometabolic disorders to metabolic syndrome and cancer. Representing many other signaling processes from homeostasis to proliferation, compartmentalization, and differentiation like Wnt and Notch, the signal cascade is elicited via a regulated intramembrane proteolysis (RIP), i. e. the proteolytic cleavage of a membrane-integral transcription factor. In this work, Linser et al. find that the membrane-spanning part of the SREBP transcriptional activator precursor molecule, which is the substrate in the RIP process, comprises interrupted structural stability. This enables conformational flexibility and maybe one of the factors explaining the enigmatic specificity and selectivity of the eminent and evolutionarily conserved RIP process, which is poorly understood to-date.
Figure Legend: Dynamics of the substrate, enabled by interrupted structural definition, may play a role for the specificity in Regulated Intramembrane Proteolysis. Many molecular details of this evolutionarily conserved mechanism are still enigmatic, even though it is a constituent of numerous signaling cascades. This work was pursued in the case of SREBP signaling, which is a hallmark of numerous pathological conditions from cardiometabolic disorders to cancer.
Linser R1, Salvi N2, Briones R3, Rovó P4, de Groot BL3, Wagner G5.[expand title=”Show Affiliations”]
- Department NMR-Based Structural Biology, Max-Planck Institute for Biophysical Chemistry, 37077 Göttingen, Germany; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115; [email protected] [email protected]
- Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115; Université Grenoble Alpes, Centre National de la Recherche Scientifique, and Commissariat à l’Énergie Atomique et aux Énergies Alternatives, Institut de Biologie Structurale, F-38044 Grenoble, France;
- Biomolecular Dynamics Group, Max-Planck Institute for Biophysical Chemistry, 37077 Göttingen, Germany.
- Department NMR-Based Structural Biology, Max-Planck Institute for Biophysical Chemistry, 37077 Göttingen, Germany;
- Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115; [email protected] [email protected] [/expand]
Regulated intramembrane proteolysis (RIP) is a conserved mechanism crucial for numerous cellular processes, including signaling, transcriptional regulation, axon guidance, cell adhesion, cellular stress responses, and transmembrane protein fragment degradation. Importantly, it is relevant in various diseases including Alzheimer’s disease, cardiovascular diseases, and cancers. Even though a number of structures of different intramembrane proteases have been solved recently, fundamental questions concerning mechanistic underpinnings of RIP and therapeutic interventions remain. In particular, this includes substrate recognition, what properties render a given substrate amenable for RIP, and how the lipid environment affects the substrate cleavage. Members of the sterol regulatory element-binding protein (SREBP) family of transcription factors are critical regulators of genes involved in cholesterol/lipid homeostasis. After site-1 protease cleavage of the inactive SREBP transmembrane precursor protein, RIP of the anchor intermediate by site-2 protease generates the mature transcription factor. In this work, we have investigated the labile anchor intermediate of SREBP-1 using NMR spectroscopy. Surprisingly, NMR chemical shifts, site-resolved solvent exposure, and relaxation studies show that the cleavage site of the lipid-signaling protein intermediate bears rigid α-helical topology. An evolutionary conserved motif, by contrast, interrupts the secondary structure ∼9-10 residues C-terminal of the scissile bond and acts as an inducer of conformational flexibility within the carboxyl-terminal transmembrane region. These results are consistent with molecular dynamics simulations. Topology, stability, and site-resolved dynamics data suggest that the cleavage of the α-helical substrate in the case of RIP may be associated with a hinge motion triggered by the molecular environment.Go To Proc Natl Acad Sci U S A